DESCRIPTION (provided by investigator): The long-range goal of the proposed project is to identify genes that regulate sleep and wakefulness in vertebrates. We will use zebrafish as a genetic system for such studies, because fish have the basic brain structures and peptides that regulate sleep in humans. We have developed high-throughput assays to measure sleep and wakefulness in zebrafish and found that the role of Hypocretin/Orexin signaling is conserved between zebrafish and mammals. We will screen 1,000 different zebrafish lines harboring disruptive insertions in genes that are expressed in the adult brain and have the potential to be drug targets. Mutants will be screened for defects in sleep and wakefulness using locomotor activity and arousal threshold. These studies will identify genes involved in sleep biology and provide functional data for a large number of biomedically relevant genes. PUBLIC HEALTH RELEVANCE: As many as 10% of Americans suffer chronic sleep disturbances, but the genetic mechanisms that control sleep and wake states remain largely unknown. The discovery of genes that regulate sleep in zebrafish will help to uncover the molecular underpinnings of sleep and inform strategies for the treatment of sleep disorders.